The abuse of prescription narcotic drugs alone in the U.S. is presently an enormous problem. The latest available data indicates that in 2011 there were 488,004 emergency department visits (1337 per day) involving nonmedical use of prescription narcotics alone, a 282% increase from 2004. ER episodes from oxycodone (oxycontin) alone increased 220% during this period. In addition, as controls on prescription narcotics are tightened dependent users are turning to the much cheaper heroin (per dose). The recent increasing appearance of fentanyl-heroin combinations is greatly exacerbating the overall problem and has resulted in an increasing number of fatal narcotic overdoses. These drugs exert their effects through the opioid receptor-endorphin system that consists of saturable, enantioselective, high affinity mu, delta and kappa opioid receptor types located in anatomically well defined areas of the mammalian CNS. Numerous endogenous opioid peptides (endorphins) function as the endogenous ligands for these receptors. This system mediates the analgesic, euphoric and addictive effects of narcotic drugs and contributes to regulation of numerous physiologic and behavioral functions in its normal state. Prescription opioids, heroin, and other narcotic drugs mimic some of the actions of the natural endorphins but dysregulate the system resulting in the development of narcotic tolerance and dependence among other undesired side effects. In our program to further understand the complex pharmacology of opioid drugs and develop strategies for treatment and prevention of their abuse and side effects we are pursuing several approaches. In one such approach, we are also pursuing the development of an anti-heroin vaccine for the treatment and prevention of heroin abuse. A successful vaccine of this type would suppress heroin abuse and the accompanying needle sharing and spread of HIV and hepatitis. Our design of heroin-mimetic haptens for vaccine preparation utilized the novel approach of employing metabolically stable haptens since heroin is rapidly metabolized to 6-acetylmorphine and then to morphine. We replaced the ester functions in heroin with amide and carbon-carbon bonds that are vastly more stable than the carbon-oxygen bonds in heroin. We have completed the complex chemical synthesis of 12 metabolically stable heroin-mimetic haptens and prepared and tested experimental vaccines. We also determined the optimum number of heroin mimetic molecules per molecule of our carrier protein tetanus toxoid to be 3-5. In addition we showed for one of our experimental vaccines that efficacy, but not antibody titer or affinity correlates with increasing hapten densities on tetanus toxoid, but not on CRM197 carriers. One of our experimental vaccines produced high affinity antibodies and an antibody titer of 2.5 million in the mouse. This vaccine abolished the antinociceptive effect of 1.0 mg/kg of heroin (an ED100 dose) in both the hot plate and tail flick assays for opioid agonist activity. This efficacy was still present after 15 weeks. We are continuing to prepare and evaluate experimental vaccines based on metabolically stable heroin-mimetic haptens.